V M Tronnier

Universität zu Lübeck, Lübeck Hansestadt, Schleswig-Holstein, Germany

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Publications (101)385.14 Total impact

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    ABSTRACT: Retinoic acid (RA) is required for development and homeostasis of the normal mammalian brain and may play a role in the initiation and progression of malignant brain tumors, such as the glioblastoma multiforme (GBM) and the gliosarcoma (Gsarc). The subpopulation of stem-like glioma cells (SLGCs) was shown to resist standard glioma radio-/chemotherapy and to propagate tumor regrowth. We used phenotypically distinct, self-renewing SLGC lines from six human GBMs, two Gsarcs, and two subcloned SLGC derivatives in order to investigate their responsiveness to atRA and to identify the RA-receptor (RAR) isotypes involved. In general, atRA exerted a pro-proliferative and pro-survival effect on SLGCs, though the efficacy was distinct. By means of RAR isotype-selective retinoids we disclosed that these effects were mediated by RARα and RARγ, except for one SLGC line, in which the pro-proliferative signal was induced by the RARβ-selective retinoid. Only one GBM-derived cell line (T1338) and a subpopulation of another (T1389) displayed neural differentiation in response to atRA. Differentiation of T1338 was induced by RARα and RARγ isotype-selective retinoids, associated with down-regulation of Sox2, and the failure to induce orthotopic tumors in the brains of SCID mice. The differential responsiveness of the SLGC lines appeared unrelated to the expression of RARβ, as (i) atRA augmented RAR isotype mRNA expression and particularly rarβ mRNA in all SLGC lines, (ii) rarβ promoter hypomethylation in the SLGC lines was not related to differentiation and (iii) the induction of T1338 differentiation was by RARα- and RARγ-selective ligands.
    Neuroscience 08/2014; · 3.12 Impact Factor
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    ABSTRACT: The nucleus accumbens is selected as a surgical target in deep brain stimulation for treating refractory obsessive-compulsive disorder (OCD). One of the therapeutic benefits of this procedure is that the abnormal hyper-functioning prefrontal cortex of patients with OCD is restored during stimulation. One hypothesis regarding the mechanism of deep brain stimulation is that the neuronal electrophysiological properties are directly altered by electrical stimulation; another hypothesis assumes that the stimulation induces selective neuron transmitter release, such as γ-aminobutyric acid (GABA). In this study, we used multi-electrode arrays with electrode size of 40 × 40 μm to record electrophysiological signals from the large nucleus accumbens neurons in acute rat brain slices while applying electrical stimulation simultaneously. We revealed that high-frequency stimulation (HFS, 140 Hz) suppressed the spontaneous neuronal firing rate significantly, whereas low-frequency stimulation (LFS, 10 Hz) did not. Both HFS and LFS have no effect on neuronal firing pattern or on neuronal oscillation synchrony. GABAB receptor antagonism reversed the HFS-provoked neuronal inhibition, whereas GABAA receptor blockade failed to affect it. The recorded neurons were pharmacologically identified to be cholinergic interneurons. We propose that HFS has a direct suppressive effect on the identified accumbal acetylcholine (ACh) interneurons by enhancing GABA release in the stimulated region. Potentially, suppressed ACh interneurons decrease the disinhibiting function of medium-sized spiny neurons in the striato-thalamo-cortical circuit. This finding might give an indication of the mechanism of the therapeutic effect of HFS in nucleus accumbens on restoring the abnormal hyperactive prefrontal cortex status in OCD.
    European Journal of Neuroscience 08/2014; in press. · 3.75 Impact Factor
  • Kai Bötzel, Volker Tronnier, Thomas Gasser
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    ABSTRACT: Essential tremor is the most common type of tremor, with a prevalence of 0.4% in the overall population and 4-7% in persons over age 65. In general, tremor is so common that patients with tremor are frequently treated not only by neurologists, but also by physicians from other specialties. This review is based on publications retrieved by a selective PubMed search and on guidelines from Germany and abroad. Particular tremor syndromes are usually diagnosed on the basis of their typical clinical presentation and whatever accompanying manifestations may be present. Ancillary tests are usually unnecessary. Unilateral rest tremor accompanied by rigidity and bradykinesia is typical of Parkinson's disease. Essential tremor is a bilateral postural tremor. The most common cause of intention tremor is multiple sclerosis. Mild tremor syndromes can often be treated satisfactorily with drugs. In case of severe tremor, which is rarer, a stereotactic operation can be considered. The usual outcome of such procedures is the complete suppression of tremor. Most patients with tremor can be given a precise diagnosis and offered specific treatment. It is important for the physician to inform the patient about the expected course of tremor over time, its possible genetic causes, and the various available treatments.
    Deutsches Ärzteblatt International 03/2014; 111(13):225-36. · 3.54 Impact Factor
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    ABSTRACT: This retrospective study investigated the outcome of patients with brain metastases after radiosurgery with special emphasis on prognostic impact of visible intratumoral necrosis on survival and local control. From 1998 through 2008, 149 patients with brain metastases from solid tumors were treated with stereotactic radiotherapy at Luebeck University. Median age was 58.4 years with 11%, 78%, 10% in recursive partitioning analysis (RPA) classes I, II, III, respectively. 70% had 1 metastasis, 29% 2-3 metastases, 2 patients more than 3 metastases, 71% active extracranial disease. Median volume of metastatic lesions was 4.7 cm3, median radiosurgery dose 22 Gy (single fraction). 71% of patients received additional whole-brain irradiation (WBI). All patients were analyzed regarding survival, local, distant failure and prognostic factors, side effects and changes in neurologic symptoms after radiotherapy. The type of contrast-enhancement in MR imaging was also analyzed; metastatic lesions were classified as containing necrosis if they appeared as ring-enhancing with central areas of no or minimal contrast enhancement. Median survival was 7.0 months with 1-year and 5-year survival rates of 33% and 0.4%, respectively. Tumor necrosis (ring-enhancement) was visible on pretreatment MRI scans in 56% of all lesions and lesions with necrosis were larger than non-necrotic lesions (6.7 cm3 vs. 3.2 cm3, p = 0.01). Patients with tumor necrosis had a median survival of 5.4 months, patients without tumor necrosis 7.2 months. Local control rate in the irradiated volume was 70%, median survival without local failure 17.8 months. Control in the brain outside the irradiated volume was 60%, median survival without distant failure 14.0 months. Significant prognostic factors for overall survival were KPS (p = 0.001), presence of tumor necrosis on pretreatment MRI (p = 0.001) with RPA-class and WBI reaching marginal significance (each p = 0.05). Prognostic impact of tumor necrosis remained significant if only smaller tumors with a volume below 3.5 cm3 (p = 0.03). Side effects were rare, only one patient suffered from serious acute side effects. Results of this retrospective study support that stereotactic radiotherapy is an effective treatment option for patients with metastatic brain lesions. The prognostic impact of visible tumor necrosis (ring-enhancement) on pretreatment MRI scans should be further investigated.
    Radiation Oncology 07/2013; 8(1):162. · 2.11 Impact Factor
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    ABSTRACT: Competency-based medical education is a prerequisite to prepare students for the medical profession. A mandatory professional qualification framework is a milestone towards this aim. The National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) of the German Medical Faculty Association (MFT) and the German Medical Association will constitute a basis for a core curriculum of undergraduate medical training. The Surgical Working Group on Medical Education (CAL) of the German Association of Surgeons (DGCH) aims at formulating a competency-based catalogue of learning objectives for surgical undergraduate training to bridge the gap between the NKLM and the learning objectives of individual medical faculties. This is intended to enhance the prominence and visibility of the surgical discipline in the context of medical education. On the basis of different faculty catalogues of learning objectives, the catalogue of learning objectives of the German Association of Orthopedics and Orthopedic Surgery and the Swiss Catalogue of Learning Objectives representatives of all German Surgical Associations cooperated towards a structured selection process of learning objectives and the definition of levels and areas of competencies. After completion the catalogue of learning objectives will be available online on the webpage of the DGCH.
    Der Chirurg 03/2013; · 0.52 Impact Factor
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    ABSTRACT: A well-established navigation method is one of the key conditions for successful brain surgery: it should be accurate, safe and online operable. Recent research shows that optical coherence tomography (OCT) is a potential solution for this application by providing a high resolution and small probe dimension. In this study a fiber-based spectral-domain OCT system utilizing a super-luminescent-diode with the center wavelength of 840 nm providing 14.5 μm axial resolution was used. A composite 125 μm diameter detecting probe with a gradient index (GRIN) fiber fused to a single mode fiber was employed. Signals were reconstructed into grayscale images by horizontally aligning A-scans from the same trajectory with different depths. The reconstructed images can display brain morphology along the entire trajectory. For scans of typical white matter, the signals showed a higher reflection of light intensity with lower penetration depth as well as a steeper attenuation rate compared to the scans typical for gray matter. Micro-structures such as axon bundles (70 μm) in the caudate nucleus are visible in the reconstructed images. This study explores the potential of OCT to be a navigation modality in brain surgery.
    Physics in Medicine and Biology 01/2013; 58(3):555-568. · 2.70 Impact Factor
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    ABSTRACT: A long term functional and reliable coupling between neural tissue and implanted microelectrodes is the key issue in acquiring neural electrophysiological signals or therapeutically excite neural tissue. The currently often used rigid micro-electrodes are thought to cause a severe foreign body reaction resulting in a thick glial scar and consequently a poor tissue-electrode coupling in the chronic phase. We hypothesize, that this adverse effect might be remedied by probes compliant to the soft brain tissue, i.e., replacing rigid electrodes by flexible ones. Unfortunately, this flexibility comes at the price of a low stiffness, which makes targeted low trauma implantation very challenging. In this study, we demonstrate an adaptable and simple method to implant extremely flexible microprobes even to deep areas of rat's brain. Implantation of flexible probes is achieved by rod supported stereotactic insertion fostered by a hydrogel (2% agarose in PBS) cushion on the exposed skull. We were thus able to implant very flexible micro-probes in 70 rats as deep as the rodent's subthalamic nucleus. This work describes in detail the procedures and steps needed for minimal invasive, but reliable implantation of flexible probes.
    Frontiers in Neuroengineering 01/2013; 6:6.
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    Dataset: Table1
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    ABSTRACT: Background: Cerebrospinal fluid (CSF) leaks are well-known and frequent complications of intracranial pro-cedures. Numerous studies have focused on the clinical aspects of incidence, risk factors, outcome, treatment, and prevention; however, large prospective multicenter studies are missing. The aim of this study was to prospec-tively analyze the rate of CSF leaks and their causes. Method: A total of 545 patients with a variety of intra-cranial procedures (elective and trauma) were recruited in a multicenter, prospective, observational study over a 12-month period. Results: In 545 cranial surgeries, we observed a CSF leak rate of 7.7% (n = 42) at the time of discharge from the hos-pital. Significant risk factors for CSF leaks were poste-rior fossa surgery, opened pneumatized spaces, patients younger than 66 years, size of craniotomies, craniecto-mies rather than craniotomies, remaining dura defects larger than 1 cm, and wound closure without using muscle sutures, continuous locked, or unlocked sutures. Non-significant risk factors for CSF leaks were revision crani-otomies, craniotomies for different pathologies, previous radiotherapy and/or systemic chemotherapy, augmenta-tion of dura sutures with various materials, and wound drains as well as temporary CSF drains. Conclusion: Despite the number of techniques and devel-opments for dural closure, the problem of CSF leaks remains evident and further improvement has to be made.
    Innovative Neurosurgery. 12/2012;
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    ABSTRACT: BACKGROUND: Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. METHODS: In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). FINDINGS: An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. INTERPRETATION: 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. FUNDING: Medtronic.
    The Lancet Neurology 10/2012; · 23.92 Impact Factor
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    ABSTRACT: As was proposed earlier, mobile devices may be integrated into the clinical workflow or daily activity by supporting documentary procedures or self-paced medical log keeping (Hofmann et al. 2009). However, due to security reasons up till now only dedicated workstations at the primary care provider's desk were intended to retrieve collected data from the mobile logging device. We propose an extension of this scheme to securely upload and process collected data by ad hoc web-service connections. In our case, we use a touch interfaced handheld device to assess pain levels by an elec-tronic Visual Analog Scale. The individually identifiable handheld collects and stores its patient's input, until a WLAN connection is sensed. It then transfers the data on a Cloud-located SQL based sever for further storage and competent retrieval. The communication between handheld and server is based on an authentificated, secure SHTTP protocol. This way, an authenticated, but remote computer based tool can access the data from the SQL Database for further clinical assessment. Mobile devices are used in a clinical setting to log volunteer's "pain" levels in parallel to usual physical log keeping. Data are transferred asynchronously and without user interaction to the analysis desktop by utilizing the Insti-tutes WLAN infrastructure. Given our preliminary results, it appears reasonable to utilize the usability and acceptance of modern handheld devices to asynchronously log and transfer even sensitive medical data over secure internet connec-tions.
    Biomedizinische Technik/Biomedical Engineering; 09/2012
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    ABSTRACT: The current quest for brain-machine-interfaces is hindered by the need to find a reliable solution for truly chronic brain implants. One approach to tackle that problem is not only to use flexible, mechanically compliant micro recording probes, but to enhance their acceptance in the target tissue by biologization. In order to shed light on the best modifica-tions, immunohistochemical staining of long term implants in rat brains provided thousands of images over a six month experimental phase. The current work explains the image processing method, how these images were analysed in the least ambiguous way to provide meaningful and statistically relevant results. Quantitative analysis of the images al-lowed for the comparison of changes within the image and comparison between different images.
    Biomedizinische Technik/Biomedical Engineering; 09/2012
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    ABSTRACT: Background Severe forms of primary dystonia are diffi cult to manage medically. We assessed the safety and effi cacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial.
    The Lancet Neurology 01/2012; 11(12):1029-1038. · 23.92 Impact Factor
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    ABSTRACT: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in PD. However, QoL fails to improve in a relevant proportion of patients. We studied clinical baseline and progression parameters associated with improvement in QoL after DBS. Data from a German randomized, controlled study comparing DBS (60 patients) with best medical treatment (59 patients) were analyzed. Changes in patients' QoL were assessed using the Parkinson's Disease Questionnaire (PDQ-39) at baseline and at the 6-month follow-up. For the STN-DBS patients, the changes in PDQ-39 were correlated with predefined clinical preoperative and progression parameters. Scores for QoL improved after STN-DBS for 57% of the patients, and for 43% patients, they did not improve. Patients with improvement in QoL showed significantly higher cumulative daily "off" time. Changes in the PDQ-39 showed a significant positive correlation with the cumulative daily off time at baseline. Logistic regression analysis revealed that 1 additional hour off time at baseline increases the odds for improvement on PDQ-39 by a factor of 1.33 (odds ratio). In the postoperative course, changes in the PDQ-39 significantly correlated with the reduction of cumulative daily off time, an improvement on the UPDRS (UPDRS III off), and positive mood changes. Among the baseline parameters, the cumulative daily off time is the strongest predictor for improvement in disease-related QoL after DBS. Improvement in QoL after STN-DBS is also correlated with changes in motor functions and changes in depression and anxiety.
    Movement Disorders 12/2011; 26(14):2516-21. · 5.63 Impact Factor
  • Central European neurosurgery 11/2011; 72(4):211-4. · 0.72 Impact Factor
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    ABSTRACT: Cerebrospinal fluid (CSF) leaks are well-known and frequent complications of intracranial procedures with their clinical aspects covered by numerous studies. Little, however, is known about the pharmacoeconomical aspects of this specific complication. 545 patients with a variety of intracranial procedures (elective and trauma) were recruited for a multicenter, prospective, observational study over a 13-month period. A specific pharmacoeconomic analysis was performed in 168 of these patients from the institution of the first author covering all clinical and pharmaco-economical aspects of this specific complication. Of all patients, 5.36% developed a postoperative CSF leak. Treatment of the leak required numerous diagnostic and therapeutic procedures such as reoperations (n=6), lumbar punctures (n=11) or lumbar drainages (n=4). Costs for these procedures and prolonged hospital stays nearly doubled the costs per case (€ 14 079/case without a fistula vs. € 25 499/case with a fistula). Reimbursement for the hospital covered these extra costs, but net earnings per case were diminished by € 565 in cases with a CSF leak. The authors conclude that the presence of a CSF leak after an intracranial operation - although not influencing outcome in general - results in additional diagnostic and therapeutic procedures for the patient, an enormous increase in costs for the community, and a financial loss for the hospital. Strategies to lower this complication rate should therefore urgently be developed both from a clinical and a pharmacoeconomical point of view.
    Journal of neurological surgery. Part A, Central European neurosurgery. 09/2011;
  • C Ditz, G Nowak, C Koch, H Merz, V Tronnier
    Journal of neurological surgery. Part A, Central European neurosurgery. 08/2011;
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    ABSTRACT: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in Parkinson's disease (PD). Dementia is considered as a contraindication for STN-DBS. However, no controlled study assessed the impact of STN-DBS on the QoL and motor outcome in PD patients with a borderline global cognitive impairment. We studied clinical baseline and progression parameters in a cohort of STN-DBS patients with a global cognitive score still in the non-demented range but scoring in the lowest quartile of the Mattis Dementia Rating Scale (MDRS), a measure of global cognitive functioning. Data from a German randomised controlled study comparing DBS (60 patients) with best medical treatment (BMT, 59 patients) were analysed. Changes in patients' QoL scores were assessed using the Parkinson's disease questionnaire (PDQ-39) at baseline and at the 6 months follow up. Patients were split into four groups according to their MDRS performance at baseline and these groups were compared in the context of motor outcome and QoL. Twelve out of sixty patients of the STN-DBS group scored in the lowest quartile of the MDRS (range between one hundred thirty and one hundred thirty seven points). An individual analysis revealed that 3 of 12 patients showed a clinical relevant improvement in QoL whereas the group statistics did not reveal any significant improvement in QoL measures after STN-DBS compared to the BMT group. Since this failure to improve in QoL cannot be explained by a failure to improve in motor functions, stimulation settings and psychiatric scales after STN-DBS, the failure to improve in QoL in patients with a borderline global cognitive score might be specifically related to lower cognitive functioning.
    Journal of the neurological sciences 07/2011; 310(1-2):261-6. · 2.32 Impact Factor
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    ABSTRACT: Reliable imaging of eloquent tumour-adjacent brain areas is necessary for planning function-preserving neurosurgery. This study evaluates the potential diagnostic benefits of presurgical functional magnetic resonance imaging (fMRI) in comparison to a detailed analysis of morphological MRI data. Standardised preoperative functional and structural neuroimaging was performed on 77 patients with rolandic mass lesions at 1.5 Tesla. The central region of both hemispheres was allocated using six morphological and three functional landmarks. fMRI enabled localisation of the motor hand area in 76/77 patients, which was significantly superior to analysis of structural MRI (confident localisation of motor hand area in 66/77 patients; p < 0.002). FMRI provided additional diagnostic information in 96% (tongue representation) and 97% (foot representation) of patients. FMRI-based presurgical risk assessment correlated in 88% with a positive postoperative clinical outcome. Routine presurgical FMRI allows for superior assessment of the spatial relationship between brain tumour and motor cortex compared with a very detailed analysis of structural 3D MRI, thus significantly facilitating the preoperative risk-benefit assessment and function-preserving surgery. The additional imaging time seems justified. FMRI has the potential to reduce postoperative morbidity and therefore hospitalisation time.
    European Radiology 07/2011; 21(7):1517-25. · 4.34 Impact Factor
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    ABSTRACT: The present paper introduces extensions to a novel model of tumour induced brain deformation in order to aid non-rigid registration of images displaying brain tumour pathology to a standard reference atlas. The model serves as a bio-physical prior and by that resolves the inherent irregularities that naturally arise in the considered registration problem. The proposed model is formulated in terms of a constrained optimisation problem. At this, the data term is modelled on the basis of the population density of cancerous cells obtained from the solution of an initial boundary value problem. A soft constraint allows for approximating bio-mechanical properties of brain tissue. It is demonstrated that introducing a non-linear weighting functional with respect to the computed density of cancerous cells into both – the data term and the soft constraint – allows for an adaptive control of the deformation pattern. Additionally, we explicitly penalise deformations of rigid structures and extend the numerical scheme by exploiting analytical derivatives as well as the compact support of the employed parametric deformation model during optimisation. Further, we have made available a strategy for re-orientation of diffusion tensors subject to spatial deformation.
    Proceedings of the 8th IEEE International Symposium on Biomedical Imaging: From Nano to Macro, ISBI 2011, March 30 - April 2, 2011, Chicago, Illinois, USA; 01/2011

Publication Stats

3k Citations
385.14 Total Impact Points

Institutions

  • 2013–2014
    • Universität zu Lübeck
      • Department of Neurosurgery
      Lübeck Hansestadt, Schleswig-Holstein, Germany
  • 2009–2013
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2012
    • University of Wuerzburg
      • Department of Neurology
      Würzburg, Bavaria, Germany
  • 1992–2012
    • Universität Heidelberg
      • • Department of Neurology
      • • Abteilung für Neuroradiologie
      • • University Hospital of Internal Medicine
      Heidelburg, Baden-Württemberg, Germany
  • 2007–2010
    • Universitätsklinikum Schleswig - Holstein
      • Klinik für Neurochirurgie (Kiel)
      Kiel, Schleswig-Holstein, Germany
  • 2006
    • Charité Universitätsmedizin Berlin
      • Department of Nephrology
      Berlín, Berlin, Germany
  • 2005
    • Ethianum Klinik Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 2001–2004
    • Technische Universität München
      • Neurologische Klinik und Poliklinik
      München, Bavaria, Germany